Pipeline

Our most advanced immunocytokine program is focused on IL-21, a gamma chain cytokine that is mechanistically differentiated from other clinical cytokines via STAT3 signaling. IL-21 is particularly effective in augmenting cytotoxic effector functions in CD8 and NK cells. Additionally, IL-21 maintains stem-like phenotypes in activated cell populations and dysregulates Treg suppressive effects. This program is assessing optimal cytotoxic anti-tumor pharmacodynamic effects by targeting with antibodies against CD8, PD-1 and TIGIT.​

Our second immunocytokine program is focused on IFN-α, whose central role in anti-viral responses through both innate and adaptive immunity is similarly applicable in oncology. We are assessing two localization strategies with IFN-α. The first targets myeloid and dendritic cells via LILRB4, an inhibitory receptor expressed on antigen presenting cells in the tumor micro-environment. The second targets myeloid cells in the tumor via CSF1R, where antagonizing CSF1R while delivering activating IFN-α is predicted to limit proliferation of suppressive myeloid populations while simultaneously inducing an inflammatory phenotype in those cells.​

Beyond our lead programs, we have identified additional differentiated cytokine-antibody pairs with unique mechanisms of action and well-established biology that are currently in the discovery stage. Cancer is our primary focus across all ongoing programs, but our modular immunocytokine approach can be applied to other therapeutic areas, including autoimmune disease and infectious disease.​

We continue to explore opportunities to strategically partner around these and other cytokine-antibody pairs.

We have identified over 100 well-characterized and high-value targets across numerous indications for which targeted protein degradation is a viable therapeutic strategy. We first performed basal screening to measure target binding against an internally validated library of E3 ubiquitin ligases, which generated numerous newly discovered weak (micromolar KD) interactions that may be strengthened by a small molecule glue. We selected many novel ligase-target pairs for 2-sided mutagenesis, where binding was measured for all combinations of single point mutants across the surfaces of the ligase and target. We then prioritized weak interactions that could be significantly enhanced by one or two mutations across the protein interface. We also considered tissue and cellular co-localization. Mutagenic binding data informed computational structural analysis for select pairs, where the impact of mutations on binding was used to generate high-confidence models of the interface between the two weakly interacting proteins. Finally, we selected four initial pairs for small molecule discovery, where we are pursuing multiple computational and experimental strategies in parallel.

We continue to explore opportunities to strategically partner on other ligase-target pairs and across induced proximity mechanisms of action beyond protein degradation.